New drugs follow a rigorous process from compound discovery to final approval requiring many years and many millions of dollars of investment. In recent years, the concept of the Thorough QT Study (TQT) has been developed by the International Committee on Harmonization (ICH) in their E14 Guidance document (E14). This study is done, as the name implies, to develop a thorough and a complete as possible understanding of the effects of the new compound on ventricular repolarization. In a typical TQT study, three sets of ECGs are collected. The three sets of ECGs are: patients on a placebo; patients on a known QT prolonging drug, typically Moxifloxacin, a fluoroquinolone antibiotic, with well understood QT prolonging properties, this is known as the “positive control”; and patients receiving the new drug being tested. The positive control drug can be any drug with well-known QT prolonging effects.
The total number of ECGs collected varies based on study design, but 15,000-18,000 ECGs is the generally accepted number in industry. While it is somewhat obvious that a trial would contain patients on the new compound as well as placebo, the reason for the patients on the known QT Prolonging drug is somewhat obscure. These patients are included in the trial so that when the ECGs are overread by clinician(s), it can be shown that the overreader(s) were capable of detecting the QT prolongation that is typically caused by the drug. In other words, if they did not detect the prolongation in the positive control the overreading process would be invalidated.
The cost of a TQT study is generally estimated to be between $500K and $1M dollars and involves recruiting perhaps 20-30 healthy volunteers to participate. While the group that receives Moxifloxacin is at little risk from taking the drug, they are not at zero risk of complications. Administering any drug to a healthy person that does not actually need to take it involves risks of severe allergic reaction, anaphylactic shock, arrhythmia, etc. While Moxifloxacin is generally well tolerated by patients, the drug labeling includes possible side effects such as: upset stomach; diarrhea; dizziness; headache; stomach pain; and vomiting. Numerous other side effects are also mentioned, including causing QT prolongation, of course. It would be desirable to create a system that allowed for the positive control group to be eliminated from future clinical trials while still meeting the need of having a positive control set of ECG recordings in the trial specific data set to be reviewed.